title: HDT-1, a new synthetic compound, inhibits glutamate release in rat cerebral cortex nerve terminals (synaptosomes).
abstract: OBJECTIVE
  Excessive glutamate release has been proposed to be involved in the pathogenesis of several neurological diseases. In this study, we investigated the effect of HDT-1 (3, 4, 4a, 5, 8, 8a-hexahydro-6,7-dimethyl-4a-(phenylsulfonyl)- 2-tosylisoquinolin-1(2H)-one), a novel synthetic compound, on glutamate release in rat cerebrocortical nerve terminals and explored the possible mechanism.
  
  
  METHODS
  The release of glutamate was evoked by the K+ channel blocker 4-aminopyridine (4-AP) or the high external [K+] and measured by one-line enzyme-coupled fluorometric assay. We also determined the loci at which HDT-1 impinges on cerebrocortical nerve terminals by using membrane potentialsensitive dye to assay nerve terminal excitability and depolarization, and Ca2+ indicator Fura-2 to monitor Ca2+ influx.
  
  
  RESULTS
  HDT-1 inhibited the release of glutamate evoked by 4-AP and KCl in a concentration-dependent manner. HDT-1 did not alter the resting synaptosomal membrane potential or 4-APevoked depolarization. Examination of the effect of HDT-1 on cytosolic [Ca2+] revealed that the diminution of glutamate release could be attributed to reduction in voltage-dependent Ca2+ influx. Consistent with this, the HDT-1-mediated inhibition of glutamate release was significantly prevented in synaptosomes pretreated with the N- and P/Q-type Ca2+ channel blocker omega-conotoxin MVIIC.
  
  
  CONCLUSIONS
  In rat cerebrocortical nerve terminals, HDT-1 inhibits glutamate release through a reduction of voltage-dependent Ca2+ channel activity and subsequent decrease of Ca2+ influx into nerve terminals, rather than any upstream effect on nerve terminal excitability.
authors.affiliation: School of Medicine, Fu Jen Catholic University, Taipei Hsien, Taiwan 24205, China. med0003@mail.fju.edu.tw
authors.forename: Su-jane
authors.initials: SJ
authors.lastname: Wang
authors.forename: Shiu-huey
authors.initials: SH
authors.lastname: Chou
authors.forename: Yuh-chi
authors.initials: YC
authors.lastname: Kuo
authors.forename: Shang-shing Peter
authors.initials: SS
authors.lastname: Chou
authors.forename: Woan-fang
authors.initials: WF
authors.lastname: Tzeng
authors.forename: Jxh-yih
authors.initials: JY
authors.lastname: Leu
authors.forename: Rwei-fen S
authors.initials: RF
authors.lastname: Huang
authors.forename: Yih-fong
authors.initials: YF
authors.lastname: Liew
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
chemical_list: C540112:3, 4, 4a, 5, 8, 8a-hexahydro-6,7-dimethyl-4a-(phenylsulfonyl)-2-tosylisoquinolin- 1(2H)-one; D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D026902:Potassium Channel Blockers; D018698:Glutamic Acid; D011189:Potassium Chloride; D015761:4-Aminopyridine; D002118:Calcium